The Brazilians will once again not feature in the first preliminary round as they one of the top-ranked sides in the tournament, but Usuthu start their debut campaign in the tournament with a clash against Nyasa Big Bullets.
Should Benni McCarthy's charges get past the Malawian outfit, they will face TP Mazembe in the next round while Sundowns await the winner of the tie between Bouenguidi Sports and AS Maniema Union.
Moving to the Confederation Cup, debutants Marumo Gallants begin their continental journey Futuro Kings from Equatorial Guniea after winning the Nedbank Cup last season.
Orlando Pirates, meanwhile, have been given a bye in the first round due their ranking, but will face the winner between Bumamuru FC and Diables Noirs.
The first round officially gets underway on 10 September 2021, CAF have confirmed.
AmaZulu v Nyasa Big Bullets
Mamelodi Sundowns *Bye
Futuro Kings v Marumo Gallants
Orlando Pirates *Bye